Hematopoietic cells play prominently in the pathogenesis of ischemia-reperfusion (IR) injury. The mechanisms by which neutrophil activation and recruitment that contribute to renal IR are only partially understood. Accumulating evidence suggests T lymphocytes play a direct role in determining the full expression of neutrophil-mediated tissue injury. Studies from our laboratories demonstrated that selective agonists of A2a-adenosine receptors (A2a-ARs) suppress inflammation and greatly reduce renal IR injury, an effect that appears to be mediated primarily by direct action on hematopoietic cells. Our proposed studies will define the role of T-cells in renal IR and their importance as a target of A2a agonist in mediating tissue protection. Accordingly we hypothesize that: 1) Activation of T-cells is a critical event for the full expression of neutrophil-mediated IR injury and 2) A2a-AR agonists mediate tissue protection from renal IR injury by selective activation of T- cells. Aim 1 will examine the kinetics and magnitude of leukocyte (CD4 +, CD8+, macrophage, and mast cell) infiltration in kidney. In this way we can characterize T-cells in relation to other hematopoietic cell lineages. A2a-agonists mediate tissue protection by action on hematopoietic cells, thus we can use these compounds as tools to examine critical components of the inflammatory cascade that contribute to renal IR injury. Aim 2 will test the hypothesis that A2a-agonist induced tissue protection is mediate primarily by action on T-cells. Alternatively action on myeloid cells could mediate tissue protection. Deletion of A2a-ARs on T-cells (lckCre adora2a f1/f1) and myeloid cell lineage (LysMCre adora2a f1/f1) will be used. A direct link between A2a-agonist effect and target cell will be established. Aim 3 will test the hypothesis that A2a-ARs modulates T-cell trafficking following renal IR injury by regulating T-cell chemokine receptors. We will examine: 1) the effect of A2a-ARs expressed on T-cell migration in response to chemokines and 2) the effect of A2a-ARs on surface expression of chemokine receptors. Our experimental approach will use whole animals, genetically altered mice, cell culture and molecular biology to define the contribution of T-cells to the pathogenesis of IR injury and define the target of A2a-agonists that are responsible for renal tissue protection.